Compositions and methods for the treatment of gastrointestinal polyps

ABSTRACT

The disclosures herein provide compounds of formula I, formula II, formula III, formula IV, formula V and formula VI or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal polyps or its associated complications.

PRIORITY

The present application is a continuation of U.S. application Ser. No.16/348,954, filed May 10, 2019, which is a 371 national stage filing ofInternational Patent Application No. PCT/IB2017/052241 filed on Apr. 19,2017, which claims the benefit of Indian Provisional Patent ApplicationNo. 201641038684 filed on Nov. 11, 2016, the entire disclosures of whichare relied on for all purposes and are incorporated into thisapplication by reference.

FIELD OF THE INVENTION

This disclosure generally relates to compounds and compositions for thetreatment of gastrointestinal polyps. More particularly, this inventionrelates to treating subjects with a pharmaceutically acceptable dose ofcompounds, crystals, solvates, enantiomer, stereoisomer, esters, salts,hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

Familial adenomatous polyposis (FAP) accounts for approximately 1% ofall large intestinal tumour diagnoses. The disease occurs de novo withthe frequency of somewhere between 1 in 8000 to 1 in 10000 births andthe age of disease penetrance varies quite considerably even betweensiblings.

FAP symptoms occur earlier than in the most common hereditarypredisposition to colorectal cancer, Lynch syndrome and generally startto appear in the second decade of life. Patients have, however beenreported to be as young as 5 years of age and in the group of ouryoungest patients, one was only 3 years old when polyps were diagnosed.The APC gene is a tumour suppressor gene that is involved in the controlof 0-catenin. Loss of APC function results in the constitutiveactivation of β-catenin, which culminates in cellular proliferation.

At the present time patients at risk of disease are screened bysigmoidoscopy every 12 months beginning at puberty. This makes itpossible to discover symptoms long before the development of an invasiveneoplasm. Once polyps appear, the only effective measure to prevent theoccurrence of the malignant disease is to remove surgically the entirecolon and rectum. Prophylactic colectomy performed at an appropriate ageprolongs the life expectancy of FAP patients, on average, from 45 toover 60 years of age.

Chemoprevention using NSAIDs has been proposed in FAP patients. Thefirst drug that was shown to be effective in FAP was sulindac. Long-termuse of this drug reduced the number of colorectal adenomas by >50% inthe colon as well as in the rectum of patients after colectomy, but notin duodenal polyposis. However, sulindac does not prevent thedevelopment of adenomas in FAP. Selective COX-2 inhibitor(cyclooxygenase-2) celecoxib, associated with fewer gastrointestinalside effects than sulindac, was found to reduce the number of colorectaladenomas by 28%, and also reduced the number of duodenal adenomas.However, cardiovascular effects (myocardial infarction or stroke) havebeen described in long-term users of another selective COX-2 inhibitor(rofecoxib), and therefore the role of these drugs remain controversial,and should be considered only in selected patients withoutcardiovascular risk factors.

There is currently a need in the art for new compositions to treatmentor delay of the onset of gastrointestinal polyps and its associatedcomplications progression.

SUMMARY OF INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods for using the same to treat, prevent and/orameliorate the effects of the conditions such as gastrointestinalpolyps.

The invention herein provides compositions comprising of formula I orpharmaceutical acceptable salts thereof. The invention also providespharmaceutical compositions comprising one or more compounds of formulaI or intermediates thereof and one or more of pharmaceuticallyacceptable carriers, vehicles or diluents. These compositions may beused in the treatment of gastrointestinal polyps and its associatedcomplications.

In certain embodiments, the present invention relates to the compoundsand compositions of formula I, or pharmaceutically acceptable saltsthereof,

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³, R⁵ each independently represents OD, OCH₃, OCOCH₃, NULL,

R¹, R⁴, R⁶ each independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula II are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents OD, OCH₃, OCOCH₃, NULL,

R² independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula III are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents OD, OCH₃, OCOCH₃, NULL,

R² independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula IV are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents OD, OCH₃, OCOCH₃, NULL,

R² independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula V are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents OD, OCH₃, OCOCH₃, NULL,

R² independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula VI are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³ independently represents OD, OCH₃, OCOCH₃, NULL,

R², R⁴ independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of gastrointestinal polyps or itsrelated complications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated forsystemic administration, oral administration, sustained release,parenteral administration, injection, subdermal administration, ortransdermal administration.

Herein, the application additionally provides kits comprising thepharmaceutical compositions described herein. The kits may furthercomprise instructions for use in the treatment of gastrointestinalpolyps or its related complications.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from gastrointestinal polyps or its related complicationsmanifested from metabolic or genetic conditions or disorders,gastrointestinal polyps, chronic diseases or disorders;neurodegenerative disorders, Hepatology, Cancer, Respiratory,Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular orOcular complications.

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1 shows an NMR spectra of Example 1 compound CLX-SYN-G157-C01.

FIG. 2 shows an NMR spectra of Example 1 compound CLX-SYN-G157-C01.

FIG. 3 shows an NMR spectra of Example 2 compound CLX-SYN-G157-CO3.

FIG. 4 shows an NMR spectra of Example 2 compound CLX-SYN-G157-CO3.

FIG. 5 shows an NMR spectra of Example 3 compound CLX-SYN-G157-CO5.

FIG. 6 shows an NMR spectra of Example 3 compound CLX-SYN-G157-CO5.

FIG. 7 shows an NMR spectra of Example 4 compound CLX-SYN-G157-CO6.

FIG. 8 shows an NMR spectra of Example 4 compound CLX-SYN-G157-CO6.

FIG. 9 shows an NMR spectra of Example 5 compound CLX-SYN-G157-CO7.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable salts. The compounds of the presentinvention can also be present in the form of pharmaceutically acceptableesters (i.e., the methyl and ethyl esters of the acids of formula I,formula II, formula III, formula IV, formula V or formula VI to be usedas prodrugs). The compounds of the present invention can also besolvated, i.e. hydrated. The solvation can be affected in the course ofthe manufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula I,formula II, formula III, formula IV, formula V or formula VI(hydration).

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, ingold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityrelated diseases patient will suffer from abnormalities or complicationand/or terminal bowel disease or failure and/or death (i.e. mortality)within a defined time window (predictive window) in the future. Themortality may be caused by the central nervous system or complication.The predictive window is an interval in which the subject will developone or more of the said complications according to the predictedprobability. The predictive window may be the entire remaining lifespanof the subject upon analysis by the method of the present invention.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating the metabolic syndrome and diabetes related disordersincludes such as gastrointestinal polyps includes such as fundic glandpolyps, hyperplastic polyps, gastric adenomas (raised intraepithelialneoplasia), gastrointestinal stromal tumors, inflammatory fibroidpolyps, gastric neuroendocrine tumors (carcinoids),bannayan-riley-ruvalcaba syndrome, cowden syndrome, familial adenomatouspolyposis, juvenile polyposis syndrome, coeliac disease, fructosemalabsorption, mild infections, parasitic infections like giardiasis,several inflammatory bowel diseases, bile acid malabsorption, functionalchronic constipation, small intestinal bacterial overgrowth, and chronicfunctional abdominal pain and other related diseases or any othermedical condition, is well understood in the art, and includesadministration of a composition which reduces the frequency of, ordelays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition. of asubject by administration of an agent even though such agent does nottreat the cause of the condition. The term “treating”, “treat” or“treatment” as used herein includes curative, preventative (e.g.,prophylactic), adjunct and palliative treatment.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the salts and compositions from the subject compositions. It isto be noted that dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. Typically, dosing will be determined using techniquesknown to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular salt or composition may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive salt and/or composition, for a sustained or extended period (ascompared to the release from a bolus). This release may result inprolonged delivery of therapeutically effective amounts of any of thetherapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable salts of saidprodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof Formula I, formula II, formula III, formula IV, formula V or formulaVI may be formulated for systemic or topical or oral administration. Thepharmaceutical composition may be also formulated for oraladministration, oral solution, injection, subdermal administration, ortransdermal administration. The pharmaceutical composition may furthercomprise at least one of a pharmaceutically acceptable stabilizer,diluent, surfactant, filler, binder, and lubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (Formula I andFormula II) to be delivered in an amount sufficient to deliver to apatient a therapeutically effective amount of a compound of formula I,formula II, formula III, formula IV, formula V or formula VI orcomposition as part of a prophylactic or therapeutic treatment. Thedesired concentration of formula I, formula II, formula III, formula IV,formula V or formula VI or its pharmaceutical acceptable salts willdepend on absorption, inactivation, and excretion rates of the drug aswell as the delivery rate of the salts and compositions from the subjectcompositions. It is to be noted that dosage values may also vary withthe severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula I, formula II, formula III, formulaIV, formula V or formula VI may be adjusted to accommodate variations inthe treatment parameters. Such treatment parameters include the clinicaluse to which the preparation is put, e.g., the site treated, the type ofpatient, e.g., human or non-human, adult or child, and the nature of thedisease or condition.

The concentration and/or amount of any compound of formula I, formulaII, formula III, formula IV, formula V or formula VI may be readilyidentified by routine screening in animals, e.g., rats, by screening arange of concentration and/or amounts of the material in question usingappropriate assays. Known methods are also available to assay localtissue concentrations, diffusion rates of the salts or compositions, andlocal blood flow before and after administration of therapeuticformulations disclosed herein. One such method is microdialysis, asreviewed by T. E. Robinson et al., 1991, microdialysis in theneurosciences, Techniques, volume 7, Chapter 1. The methods reviewed byRobinson may be applied, in brief, as follows. A microdialysis loop isplaced in situ in a test animal. Dialysis fluid is pumped through theloop. When compounds with formula I, formula II, formula III, formulaIV, formula V or formula VI such as those disclosed herein are injectedadjacent to the loop, released drugs are collected in the dialysate inproportion to their local tissue concentrations. The progress ofdiffusion of the salts or compositions may be determined thereby withsuitable calibration procedures using known concentrations of salts orcompositions.

In certain embodiments, the dosage of the subject compounds of formulaI, formula II, formula III, formula IV, formula V or formula VI providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of Formulas I is in the range ofabout 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses,for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divideddoses. The compounds of Formulas I may be administered at a dose of, forexample, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.Compounds of Formula I, formula II, formula III, formula IV, formula Vor formula VI may also be administered to a human patient at a dose of,for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or lessthan 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000,2000, 5000 mg per day. In certain embodiments, the compositions hereinare administered at an amount that is less than 95%, 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, or 10% of the compound of formula I, formula II,formula III, formula IV, formula V or formula VI required for the sametherapeutic benefit.

An effective amount of the compounds of formula I, formula II, formulaIII, formula IV, formula V or formula VI described herein refers to theamount of one of said salts or compositions which is capable ofinhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate,ameliorate, halt, restrain, slow or reverse the progression, or reducethe severity of a complication resulting from nerve damage ordemyelization and/or elevated reactive oxidative-nitrosative speciesand/or abnormalities in neurotransmitter homeostasis's, in patients whoare at risk for such complications. As such, these methods include bothmedical therapeutic (acute) and/or prophylactic (prevention)administration as appropriate. The amount and timing of compositionsadministered will, of course, be dependent on the subject being treated,on the severity of the affliction, on the manner of administration andon the judgment of the prescribing physician. Thus, because ofpatient-to-patient variability, the dosages given above are a guidelineand the physician may titrate doses of the drug to achieve the treatmentthat the physician considers appropriate for the patient. In consideringthe degree of treatment desired, the physician must balance a variety offactors such as age of the patient, presence of preexisting disease, aswell as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula I, formula II, formula III, formula IV, formula Vor formula VI may also comprise enterically coated comprising of variousexcipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula I, formula II, formula III, formulaIV, formula V or formula VI disclosed herein, for instance, compounds offormula I, formula II, formula III, formula IV, formula V or formula VIor pharmaceutical acceptable salts of a compounds of formula I, formulaII, formula III, formula IV, formula V or formula VI.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of theneurological disease; the type of host involved, including its age,health and weight; the kind of concurrent treatment, if any; thefrequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof. Suitable glidants include,but are not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirsalts, and mixtures thereof. Examples of suitable fatty acid estersinclude, but are not limited to, sucrose fatty acid esters, mono-, di-,and triglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoylmacrogol-32 glycerides, and mixtures thereof. Examples of suitablephospholipids include phosphotidyl choline, phosphotidyl serene,phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examplesof suitable waxes include, but are not limited to, carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate, andmixtures thereof. Examples of super disintegrants include, but are notlimited to, croscarmellose sodium, sodium starch glycolate andcross-linked povidone (crospovidone). In one embodiment the tablet corecontains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are well known anddescribed in die art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer which is insoluble in the acidenvironment of the stomach, but soluble in the neutral environment ofsmall intestines. The delayed release dosage units can be prepared, forexample, by coating a drug or a drug-containing composition with aselected coating material. The drug-containing composition may be atablet for incorporation into a capsule, a tablet for use as an innercore in a “coated core” dosage form, or a plurality of drug-containingbeads, particles or granules, for incorporation into either a tablet orcapsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent. In one embodiment of dosage forms that mimic a twice daily dosingprofile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60wt. %, of the total amount of active agent in the dosage form isreleased in the initial pulse, and, correspondingly approximately 70 wt.% to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount ofactive agent in the dosage form is released in the second pulse. Fordosage forms mimicking the twice daily dosing profile, the second pulseis preferably released approximately 3 hours to less than 14 hours, andmore preferably approximately 5 hours to 12 hours, followingadministration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of formula I, formula II, formula III,formula IV, formula V or formula VI or other active agents are known, orwill be apparent in light of this disclosure, to those skilled in thisart. For examples of methods of preparing pharmaceutical compositions,see Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof a subject composition which may be combined with a carrier materialto produce a single dose may vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association subject compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a subject composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

The compounds of formula I, formula II, formula III, formula IV, formulaV or formula VI described herein may be administered in inhalant oraerosol formulations. The inhalant or aerosol formulations may compriseone or more agents, such as adjuvants, diagnostic agents, imagingagents, or therapeutic agents useful in inhalation therapy. The finalaerosol formulation may for example contain 0.005-90% w/w, for instance0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to thetotal weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the subject compositions, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax, or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the appropriate body cavity and release theencapsulated compound(s) and composition(s). Formulations which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams, or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermalpatch are known in the art. Exemplary patches and methods of patchdelivery are described in U.S. Pat. Nos. 6,974,588, 6,564,093,6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer. A method for the manufacture of the above-mentioned substratesheet comprises preparing the above resin composition molding the resincomposition into a composite film by a calendar process, and thenadhering a polyalkylene terephthalate film on one side of the compositefilm by means of an adhesive layer thereby forming the substrate sheet,and forming a primer layer comprising a saturated polyester resin on theouter surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in apharmaceutically acceptable adhesive and laminating the drug-containingadhesive onto a suitable backing member, e.g. a polyester backingmembrane. The drug should be present at a concentration which will notaffect the adhesive properties, and at the same time deliver therequired clinical dose.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the newlydeveloped proteins and peptide drugs are too large to be deliveredthrough passive transdermal patches and may be delivered usingtechnology such as electrical assist (iontophoresis) for large-moleculedrugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

In some cases, it may be desirable to administer in the form of a kit,it may comprise a container for containing the separate compositionssuch as a divided bottle or a divided foil packet. Typically the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a plastic material that may betransparent.

Methods and compositions for the treatment of gastrointestinal polyps.Among other things, herein is provided a method of treatinggastrointestinal polyps, comprising administering to a patient in needthereof a therapeutically effective amount of compound of Formula I.

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³, R⁵ each independently represents OD, OCH₃, OCOCH₃, NULL,

R², R⁴, R⁶ each independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

Methods of Making

Examples of synthetic pathways useful for making compounds of formula Iare set forth in example below and generalized in scheme 1, scheme 2,scheme 3, scheme 4 and scheme 5:

Preparation of2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoic acid(Step-1)

To a stirred solution of Eflornithine.HCl (30 g, 137.26 mmol) in THF/H₂O(480 mL, 1:1 v/v) was added NaHCO₃ (40.3 g, 480.32 mmol) followed by(Boc)₂O (3.89 g, 178.34 mmol) and stirred the reaction mixture at RT for48 h. The progress of the reaction was monitored by TLC. THF was removedunder reduced pressure; the aqueous layer was neutralized with 1 N HCland concentrated under reduced pressure. The residue was triturated with15% MeOH/CH₂Cl₂ and the insoluble material was filtered. The filtratewas concentrated under reduced pressure to afford2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoic acid(28 g, 73% yield) as white solid.

Preparation of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoate(Step-2)

To a stirred solution of2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl) pentanoic acid(12 g, 42.55 mmol) in DMF (100 mL) was added DIPEA (27.44 g, 212.75mmol), solketal (5.62 g, 42.55 mmol) followed by HATU (19.40 g, 51.06mmol) and stirred the reaction mixture at RT for 4 h. The progress ofthe reaction was monitored by TLC. The reaction mixture was poured intoice-cold water (500 mL), extracted with ethyl acetate (2×300 mL). Thecombined organic layer was washed with water (3×200 mL), dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude compound was purified by column chromatography (silica gel 100-200mesh, eluted with 15-40% EtOAc in Hexane) to afford(2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl) pentanoate(5.5 g, 32% yield) as colorless liquid.

Preparation of 2,3-dihydroxypropyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoate(Step-3)

To a stirred solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl) pentanoate(5.5 g, 13.88 mmol) in MeOH (60 mL) was added PTSA (2.63 g, 13.88 mmol)and stirred the reaction mixture at RT for 20 h. The progress of thereaction was monitored by TLC. The reaction mixture was concentratedunder reduced pressure, the residue was diluted with H₂O (50 mL),basified with saturated NaHCO₃ solution, extracted with 10% MeOH/CH₂Cl₂(4×200 mL). The combined organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The crude compound waspurified by column chromatography (silica gel 100-200 mesh, eluted with2-5% MeOH in CH₂Cl₂) to afford 2,3-dihydroxypropyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoate (3.7g, 75% yield) as colorless liquid.

Preparation of(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoyl)oxy)propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) (Step-4)

To a stirred solution of 2,3-dihydroxypropyl2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl) pentanoate(3.7 g, 10.38 mmol) in DMF (32 mL) was added EPA (6.90 g, 22.89 mmol),EDC.HCl (4.78 g, 24.91 mmol) followed by DMAP (506 mg, 4.15 mmol) andstirred the reaction mixture at RT for 20 h. The progress of thereaction was monitored by TLC. The reaction mixture was diluted withEtOAc (500 mL), washed with H₂O (3×200 mL), dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The crude compound waspurified by column chromatography (silica gel 100-200 mesh, eluted with15-20% EtOAc in Hexane) to afford(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoyl)oxy)propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) (3 g, 31% yield) as yellow liquid.

Preparation of(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2,5-diamino-2-(difluoromethyl)pentanoyl)oxy) propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate)hydrochloride (Step-5)

To a stirred solution of(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2-amino-5-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)pentanoyl)oxy)propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate) (7 g,7.56 mmol) in 1,4-dioxane (50 mL) was added HCl in 1,4-dioxane (4M, 60mL) and stirred the reaction mixture at RT for 2 h. The progress of thereaction was monitored by TLC. The reaction mixture was concentrated,co-distilled with CH₂Cl₂ to afford(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2,5-diamino-2-(difluoromethyl)pentanoyl)oxy)propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) hydrochloride (6.5 g) as brown gummysolid with 99.08% of HPLC purity.

Preparation of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-((3-chloro-2-methylphenyl)amino)benzoate (Step-1)

To a stirred solution of Solketal (6 g, 45.93 mmol), Tolfenamic acid(13.04 g, 49.97 mmol) in CH₂Cl₂ (120 mL) was added DCC (11 g, 54 mmol)followed by DMAP (549 mg, 4.50 mmol) and stirred the reaction mixture atRT for 3 h. The progress of the reaction was monitored by TLC. Thereaction mixture was diluted with CH₂Cl₂ (50 mL), filtered through a padof celite, washed with CH₂Cl₂ (30 mL). The filtrate was concentratedunder reduced pressure. The crude compound was purified by columnchromatography (silica gel 100-200 mesh, eluted with 1% EtOAc in Hexane)to afford (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-((3-chloro-2-methylphenyl) amino) benzoate (11 g, 64% yield) as pale yellow liquid.

Preparation of 2,3-dihydroxypropyl2-(3-chloro-2-methylphenylamino)benzoate (Step-2)

A mixture of(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-((3-chloro-2-methylphenyl)amino)benzoate (8 g, 21.33 mmol) and 80% Acetic acid/H₂O (80 mL) werestirred at 80° C. for 3 h. The progress of the reaction was monitored byTLC. The reaction mixture was poured into ice-cold water (800 mL); thesolid formed was filtered and dried under vacuum to afford2,3-dihydroxypropyl-2-((3-chloro-2-methylphenylamino)benzoate (5.4 g,75% yield) as off white solid.

Preparation of(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2-((3-chloro-2-methylphenyl)amino) benzoyl) oxy) propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) (Step-3)

To a stirred solution of 2,3-dihydroxypropyl2-((3-chloro-2-methylphenyl)amino)benzoate (3 g, 8.95 mmol) in CH₂Cl₂(60 mL) was added EPA (5.95 g, 19.70 mmol), DCC (4.06 g, 19.70 mmol)followed by DMAP (0.109 g, 0.89 mmol) and stirred the reaction mixtureat RT for 16 h. The progress of the reaction was monitored by TLC. Thereaction mixture was diluted with CH₂Cl₂ (25 mL), filtered through a padof celite, washed with CH₂Cl₂ (25 mL). The filtrate was concentratedunder reduced pressure at 30° C. to obtain crude compound.

Note: 4×3 g Batches were combined and the resultant crude compound waspurified by column chromatography (multiple times, silica gel 100-200mesh, eluted with 2% EtOAc in Hexane) to afford(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-((2-((3-chloro-2-methylphenyl)amino)benzoyl)-oxy)propane-1,2-diyl bis(icosa-5,8,11,14,17-pentaenoate)(3.3 g, 10% yield) as pale yellow liquid with 98.11% of HPLC purity.

Preparation of (Z)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate (Step-1)

To a stirred solution of Solketal (12 g, 90.90 mmol) in CH₂Cl₂ (300 mL)was added DCC (18.7 g, 90.90 mmol), DMAP (1.1 g, 9.09 mmol) followed bySulindac (32.3 g, 90.90 mmol) and stirred the reaction mixture at RT for16 h. The progress of the reaction was monitored by TLC. The reactionmixture was diluted with CH₂Cl₂ (100 ML), filtered through a pad ofcelite, washed with CH₂Cl₂ (100 mL). The filtrate was washed with water(2×100 mL). The combined organic layer was dried over anhydrous sodiumsulphate concentrated under reduced pressure. The crude compound waspurified by column chromatography (silica gel 60-120 mesh, eluted with1% MeOH in CH₂Cl₂) to afford (Z)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate (22 g, 52% yield) as yellowsemi-solid.

Preparation of (Z)-2,3-dihydroxypropyl2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate(Step-2)

A mixture of(Z)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate (15 g, 31.91 mmol) and 80% Aceticacid (150 mL) were stirred at 50° C. for 2 h. The progress of thereaction was monitored by TLC. The reaction mixture was poured intoice-cold water (1000 mL), extracted with ethyl acetate (2×300 mL). Thecombined organic layer was washed with saturated NaHCO₃ solution (3×200mL), water (100 mL), dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude compound was diluted withethyl acetate (100 mL), stirred at RT 30 min, filtered and dried undervacuum to afford (Z)-2,3-dihydroxypropyl2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate(9 g, 65% yield) as yellow solid.

Preparation of(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-(2-((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetoxy)propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) (Step-3)

To a stirred solution of (Z)-2,3-dihydroxypropyl2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate(12 g, 27.90 mmol) in DMF (240 mL) was added EPA (18.6 g, 62.39 mmol),EDC.HCl (11.8 g, 62.39 mmol) followed by DMAP (681 mg, 5.58 mmol) andstirred the reaction mixture at RT for 16 h. The progress of thereaction was monitored by TLC. The reaction mixture was filtered througha pad of celite, washed with ethyl acetate (100 mL). The filtrate wasdiluted with ethyl acetate (600 mL), washed with ice-cold water (3×250mL), brine (150 mL), dried over anhydrous sodium sulphate andconcentrated under reduced pressure at below 30° C. The crude compoundwas purified by column chromatography (multiple times, silica gel 60-120mesh, eluted with 4% EtOAc in CH₂Cl₂) followed by preparative HPLC (5%THF in Acetonitrile) to afford(5Z,5′Z,8Z,8′Z,11Z,11′Z,14Z,14′Z,17Z,17′Z)-3-(2-((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetoxy)propane-1,2-diylbis(icosa-5,8,11,14,17-pentaenoate) (4.8 g, 17% yield) as yellow liquidwith 98.77% of HPLC purity.

To a stirred solution of (5Z,8Z,11Z,14Z,17Z)-2,3-dihydroxypropyleicosa-5,8,11,14,17-pentaenoate (5 g, 14 mmol, Int-B) and2-((3-chloro-2-methyl phenyl)amino)benzoic acid (10.41 g, 30.8 mmol,Sulindac) in dry CH₂Cl₂ (100 mL), was added DCC (9.58 g, 49 mmol)followed by DMAP (649 mg, 5.6 mmol) at 0-5° C. The reaction mixture wasallowed to RT and stirred for 16 h under Argon atmosphere. The progressof the reaction was monitored by TLC. The reaction mixture was filteredthrough a pad of celite, washed with CH₂Cl₂ (30 mL). The filtrate wasconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography (silica gel 230-400 mesh, eluted with EtOAc). Theobtained compound was again purified by preparative HPLC (eluted withHPLC grade Acetonitrile) to get 2.2 g of desired compoundCLX-SYN-G157-C06, confirmed by 1H NMR.

To a stirred solution of 4-((3-ethynylphenyl)amino)quinazoline-6,7-diol(1 g, 4 mmol, Compound-5) in dry CH₂Cl₂ (20 mL) and DMF (5 mL) was addedEPA (3.27 g, 12 mmol), the reaction mixture was cooled to 0-5° C., addedEDC HCl (1.73 g, 10 mmol). The reaction mixture was allowed to RT andstirred for 4 h under Argon atmosphere. The progress of the reaction wasmonitored by TLC. The reaction mixture was quenched with cold water (30mL) stirred for 15 minutes. The reaction mass was filtered through a padof celite; separated the organic layer, dried over Na2SO4 and solventwas evaporated under reduced pressure at 30° C. The crude compound waspurified by flash column chromatography (eluted with 13% EtOAc in petether). The obtained compound (850 mg) was again purified by preparativeIPLC (eluted with IPLC grade Acetonitrile) to get 200 mg of desiredcompound CLX-SYN-G157-C07, confirmed by 1H NMR.

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating gastrointestinal polyps and their complications.While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the systems and methods herein will become apparentto those skilled in the art upon review of this specification. The fullscope of the claimed systems and methods should be determined byreference to the claims, along with their full scope of equivalents, andthe specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

What is claimed is:
 1. A compound of Formula I:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof; wherein R₁, R₃, and R₅ eachindependently represents NULL,

R₂, R₄, and R₆ each independently represents

n is independently 1, 2, 3, 4 or 5; a is independently 2, 3 or 7; each bis independently 3, 5 or 6; e is independently 1, 2 or 6; c and d areeach independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or —COCH₃.
 2. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 3. The pharmaceutical compositionof claim 2, wherein said pharmaceutical composition is formulated totreat a patient in need with an effective amount administering thepatient in need by oral administration, delayed release, sustainedrelease, transmucosal administration, syrup, topical administration,parenteral administration, injection, subdermal administration, oralsolution, rectal administration, buccal administration, or transdermaladministration.
 4. The pharmaceutical composition of claim 3 formulatedfor the treatment of gastrointestinal polyps, intestinal polyps andinflammation.
 5. A method of treating at least one of a gastrointestinalpolyps, intestinal polyps and inflammatory disease comprising:administering the compound of claim 1 to patient suffering from at leastone of a gastrointestinal polyps, intestinal polyps and inflammatorydisease, wherein said compound of claim 1 is selected from the groupconsisting of


6. A compound of claim 1 selected from the group consisting of:
 7. Apharmaceutical composition comprising a compound of claim 6, and apharmaceutically acceptable carrier.
 8. The pharmaceutical compositionof claim 7, wherein said pharmaceutical composition is formulated totreat a patient in need with an effective amount administering thepatient in need by oral administration, delayed release, sustainedrelease, transmucosal administration, syrup, topical administration,parenteral administration, injection, subdermal administration, oralsolution, rectal administration, buccal administration, or transdermaladministration.
 9. The pharmaceutical composition of claim 8 formulatedfor the treatment of gastrointestinal polyps, intestinal polyps andinflammation.